This project is designed to investigate the effect of acute and chronic oral administration and the withdrawal/washout of therapeutic levels of lithium, nortriptyline, and placebo on HPA axis function in control subjects. Thirty-six healthy male controls will undergo 8 ovine corticotropin releasing hormone (oCRH) tests; 36 will have 8 insulin tolerance tests (ITTs); and 36 will have 6 dexamethasone suppression tests (DSTs) and 3 lumbar punctures (LPs). In each group of 36, 12 will be randomly and blindly assigned to each of the experimental substances. Repetitive testing will occur before substance administration, acutely after starting the substance, at 2 and 4 weeks on the medication, immediately after withdrawing the substance, and 2 and 4 weeks during washout. By performing the oCRH test, the ITT, and the DST/LP it will be possible to assess the effect of medication on hypothalamic stimulation of the pituitary (ITT), exogenous stimulation of the pituitary (oCRH), feedback inhibition (DST), and CSF CRH levels. Assessment of adrenal response will also be possible by comparing the log ACTH/cortisol ratio. The basic measurements of HPA axis function will include CSF CRH, plasma ACTH, and plasma cortisol. It will also be possible in this project to assess the affect of medication on corticosterone (mineralocorticoid pathway), androstendione (adrenal androgen pathway), and 11 B hydroxyandrostendione (cortisol metabolite associated with psychotic depression). In addition, a new time integrated salivary cortisone and cortisol measuring device (ODS) will be field tested. This grant will support a study which is essential to the progress of research in the area of HPA axis function in affective disorders. Not only will it provide needed information about the role of psychiatric medication in altering HPA axis function thus allowing better interpretation of existing studies and better formulation of studies in the future, it will also likely lead to a decrease in the cost of such studies in the long run (thus the grant will pay for itself) and allow the formulation of studies which otherwise could not be performed in psychiatrically ill patients. Since there is a possibility that hypercortisolemia plays a direct role in the development of depression in a percentage of patients with depression, following through on this avenue of research is essential. Direct modulation of the HPA axis may eventually be shown helpful in this subset of patients. Furthermore, a better understanding of the mechanisms involved in this dysregulation may facilitate the identification of the source of the difficulty. This can potentially be done much more economically if the effects of medication on the HPA axis are known.